Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Ellenbroek, Johanne H.; Töns, H.A.M.; Meeteren, M. J. A. Westerouen van; Graaf, Natascha de; Hanegraaf, Maaike; Rabelink, Ton J.; Carlotti, Françoise; Koning, Eelco J.P. de

doi:10.1007/s00125-013-2957-2

Cited by 43 publications

(53 citation statements)

References 37 publications

(42 reference statements)

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“…The reduction in the beta cell mass in the RIPCreEr-EYFP mice probably reflects the elimination of almost all the INϩ cells expressing the transgene. It has been reported that normoglycemic CD-1 mice treated with liraglutide, a GLP-1r agonist, for 6 weeks had a decreased beta cell mass and in proliferation (14). In view of our present findings with bigenic mice, the observations in normoglycemic CD-1 mice suggest that the stimuli to secrete more insulin eliminated suboptimal beta cells, and that normal glucose levels was maintained by the cells still left in the islets.…”

Section: Discussionsupporting

confidence: 67%

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

Teitelman

Kedees

2015

Journal of Biological Chemistry

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Background:We tested whether insulin cells expressing an inducible RIP-Cre transgene display a normal phenotype. Results: RipCre insulin cells die when the stimulation of insulin synthesis is protracted. Conclusion: Beta cells expressing an inducible RIP-Cre transgene are functionally deficient. Significance: The use of an inducible RIPCre system to examine beta cell gene function/development could distort experimental results.

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Section: Discussionsupporting

confidence: 67%

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

Teitelman

Kedees

2015

Journal of Biological Chemistry

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“…␤-Cell cluster size was determined as the median size of ␤-cell clusters (defined as Ն4 ␤-cells per cluster) per mice. ␣-Cell mass was determined as previously described (14) by calculating the ratio of ␣-cell area to ␤-cell area, using Image J software (Image J; National Institutes of Health, Bethesda, MD) multiplied by the ␤-cell mass.…”

Section: Animalsmentioning

confidence: 99%

“…Changes in glucose metabolism are associated with adaptation of the number and/or function of ␤-cells to produce and secrete an adequate amount of insulin (6,34). Also ␣-cell mass can be modulated by dietary changes (14). Inadequate adaptation leads to glucose intolerance and eventually results in diabetes mellitus (9,21).…”

mentioning

confidence: 99%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

123

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Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced ␤-and ␣-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab 306: E552-E558, 2014. First published January 7, 2014 doi:10.1152/ajpendo.00453.2013.-High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ␤-and ␣-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1␤, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ␤-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ␤-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also ␣-cell mass was markedly decreased, resulting in a lower ␣-to ␤-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ␤-and ␣-cell mass, but no weight loss. This indicates that long-term high-fat, lowcarbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans. pancreatic islet; ketogenic diet; glucose intolerance; ␤-cell; ␣-cell

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“…Adult pancreatic islet cells are mostly in the quiescent/G 1/0 state but can re-enter cell cycle following appropriate stimuli. For example, the glucagon-like peptide-1 (GLP-1) analogue, exendin-4, stimulates beta cell proliferation [11,12] while preventing alpha cell expansion [13,14]. However, the mechanisms by which GLP-1 mediates these divergent effects in alpha and beta cells are unknown.…”

Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

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Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Cited by 43 publications

References 37 publications

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

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